Spatial deficits and hemispheric asymmetries in the rat following unilateral and bilateral lesions of posterior parietal or medial agranular cortex

Behavioural Brain Research, 50 (1992) 53-68 9 1992 Elsevier Science Publishers B.V. All rights reserved. 0166-4328/92/$05.00

53

BBR01331

Spatial deficits and hemispheric asymmetries in the rat following unilateral and bilateral lesions of posterior parietal or medial agranular cortex V o n R. K i n g ~ a n d J a m e s V. C o r w i n b aDepamnent of Psychology, University of IVisconsin, Madison, 1VI 53706 (USA) and bDepartment of Psychology, Northern Illinois University, Dekalb, IL 60115 (USA) (Received 5 February 1992) (Revised version received 25 May 1992) (Accepted 26 May 1992)

Key words: Egocentric; Allocentric; Prefrontal; Parietal; Cortex; Asymmetry; Hemispatial

Studies of spatial behavior in both the human and non-human primate have generally focused on the role of the posterior parietal and prefrontal cortices and have indicated that destruction of these regions produce allocentric and egocentric deficits, respectively. The present study examined the role of the rodent analogs of these regions, the posterior parietal (PPC) and medial agranular (AGm) cortices, in egocentric and allocentric spatial processing, and whether spatial processing in rodents is organized in a hemispatial and/or lateralized manner as has been found in the primate. Eighty male rats receiving either a unilateral or bilateral lesion of AGm or PPC were examined on an egocentric (adjacent arm) or an allocentric (cheeseboard) maze task. The results indicated that PPC and AGm have dissociable spatial functions. Bilateral AGm destruction resulted in egocentric spatial deficits, and unilateral AGm operates demonstrated an intermediate deficit. In contrast, bilateral PPC operates demonstrated a severe deficit in allocentric processing. In addition, there were lateralized differences in the performance of unilateral PPC operates. While right PPC lesions resulted in a significant deficit on the allocentric task, no such deficit was seen in left PPC operates. In addition, neither unilateral AGm nor unilateral PPC operates demonstrated a hemispatial impairment on either the egocentric or allocentric tasks.

INTRODUCTION

The perception of space is a highly complex function and it is therefore not surprising that a number of brain areas have been implicated in the control of spatial behavior. Studies of the neural mechanisms of spatial behavior in primates have generally focused on cortical areas, in particular, the prefrontal and posterior parietal ( P P C ) c o r t i c e s 46'53. Behavioral, electrophysiological, and anatomical studies have established that PPC (generally considered to be Brodmann's areas 5 and 7) plays an essential role in the perception of space in the primate. The role of PPC in spatial function appears to be related to the perception of allocentric and extrapersonal s p a c e 4'54. I n particular, patients with a right parietal lesion show a deficit on a map reading (allocentric) task, but no deficit on a personal orientation

Correspondence: V.R. King, Dept. Psychology, 1202 West Johnson, University of Wisconsin-Madison, Madison, WI 53706, USA.

task requiring individuals to touch different parts of the body 54. In addition, PPC lesions in the monkey produce deficits on allocentric and extrapersonal tasks ineluding a landmark reversal task 4s, complex string pattern identification6~ cage finding57, and a spatial sequencing task requiring the use of external cues a. Evidence also supports the role of the dorsolateral prefrontal area of the primate (generally considered to be Brodmann's areas 6, 8, 9, 10, 44, 45 and 46) in spatial behavior. In contrast to the role of the PPC in allocentric and extrapersonal spatial processing, prefrontal cortex appears to be involved in the perception of personal and egocentric space. Human patients with left anterior frontal lesions showed deficits on a personal orientation task (i.e. touching body areas based on a human body map), while no such deficit was seen on a map navigation task requiring use ofextrapersonal cues 54. In non-human primates, Poh148 demonstrated that monkeys with bilateral ablation of anterior frontal areas had deficits on a place reversal (egocentric) task but not a landmark reversal (allocentric) task, although

54 it should be noted that Brody and Pribram 3 demonstrated both extrapersonal and personal spatial deficits in monkeys with frontal lesions. Taken together, these findings suggest an allocentric-egocentric dissociation for the PPC and prefrontal cortices in the primate. The role of neocortical areas in rodent spatial behavior has been less thoroughly investigated, though both PPC and area 8 have been proposed to have rodent analogs. In particular, medial agranular cortex (AGm), the rodent analog of a r e a 840,49,50 , has behavioral, anatomical and electrophysiological characteristics similar to area 8 of the primate 8"9:7"49'5~ As with the primate, a number of studies have demonstrated that A G m functions in spatial behavior. Bilateral prefrontal lesions which include AGm result in deficits on a variety of spatial tasks (see refs. 32 and 33 for reviews). In addition, it has been well established that unilateral lesions of AGm cause severe hemispatial neglects'9'6~. Posterior parietal cortex has been proposed to have a rodent analog as well (also termed PPC), though the anatomical and behavioral data supporting the similarity between rodent and primate PPC is more limited. This paucitY of data is due in part to a lack of electrophysiological and anatomical data necessary for a precise areal definition of PPC. Using Krieg's classic cytoarchitectonic and myeloarchitectonic description of rodent cortex 3s, Kolb and Walkey 36 define area 7 as a 2-mm-wide strip of cortex beginning 2 mm lateral to the midline and situated between area 3 (somatosensory cortex) and area 18 (visual cortex). Single-unit recordings in this area revealed the presence of place cells similar to that found in the hippocampus 6. In addition, bilateral lesions of PPC result in acquisition deficits on both the Morris water and radial-arm m a z e s 14'26'28'36. In addition, Dimattia and Kesner ~5 demonstrated that PPC-lesioned animals not only had a deficit on the Morris water maze relative to control operates, but also had more severe deficits than rats with lesions of the hippocampus further supporting the role of this area in spatial behavior. While such studies support the role of A G m and PPC in spatial function, a number of questions about the cortical representation of space in the rodent remain unanswered. In particular, unilateral lesions of parietal and frontal areas in human and non-human primates have been shown to d.isrupt both simple detection of contralateral stimuli and more complex spatial behavior in both a lateralized 24'44"45 and hemispatial fashion ~'2"22. Recent studies in the rodent have shown both hemispatial and lateralized deficits in the neglect produced by unilateral A G m lesions 8"~~ and lateralized differences in open field behavior following both unilateral A G m and parietal lesions ~'55. However, only

one study has thus far examined the effects of unilateral lesions on the more complex spatial tasks typically used to test for spatial deficits following bilateral lesions. In this ease, deficits on the Morris water maze were found following fight but not left-sided PPC lesions combined with corpus callosum section 42. Data on whether the spatial representation in the rodent is hemispatial or lateralized is therefore very limited and requires further examination of the effects of unilateral lesions on complex spatial tasks. In addition to the lack of data on how space may be represented in rodent cortex, there is a paucity of evidence on whether the allocentric-egocentric or peripersonal-extrapersonal dichotomy proposed foithe primate may also be present in the rodent. In support of this dichotomy, Kesner et al. 27 found that PPClesioned rats had deficits on an allocentric task requiring rats to use extrapersonal cues for accurate navigation to a reward and AGm-lesioned rats had deficits on an egocentric task requiring the animal to discriminate the nearest from the farthest arms on a radial arm maze. In contrast, Kolb and his colleagues 34'4~ reported severe deficits following medial prefrontal lesions on the Morris water and radial arm mazes, but very mild or no deficits following a PPC lesion. These findings led to the conclusion that not only is there no egocentric-allocentric dichotomy between PPC and AGm, but also that A G m plays a greater role in spatial perception than PPC, though PPC may have a special function in accurate locomotion to targets 32. Examination of the effects of unilateral lesions on spatial behavior is therefore an important step in understanding how space is represented in rodent cortex. Therefore, the current study examined the effects of unilateral as well as bilateral AGm and PPC lesions on egocentric (adjacent arm task in a radial arm maze) and allocentric (cheeseboard) tasks. Such an investigation is not only useful in clarifying whether an allocentricegocentric dichotomy of function exists but is also useful in determining whether space is represented in a lateralized or hemispatial fashion in rodent cortex.

RADIAL ARM MAZE

Materials and methods Subjects Subjects were 40 male Long-Evans hooded rats ordered from Harlan Industries and weighing 300-350 g at the time of testing. Upon arrival the animals were housed in individual cages in a colony room on a 12:12 h

55 light-dark cycle. All rats were handled for approximately 14 days prior to behavioral testing in order to reduce struggling and 'freezing' which could interfere with behavioral testing. All rats had free access to water and were maintained at 80-85 ~ of free feeding weight throughout the experiment with the weights adjusted for normal growth. Once the weights were stable at the 80-85~o level, presurgical maze training began.

Apparatus attd environment A wooden eight arm radial maze was used to test for egocentric spatial ability z7. Each arm was 60 cm long and 9 cm in width. The walls of the arms were 5 cm in height. The choice area was an octagon 40 cm in width. The maze floor was painted flat black and the walls of the arms were flat brown. The maze was located a meter above the floor in the middle of a well lit room. The room contained a number of distinctive cues (e.g. a shelfwith a nufiaber of different objects on it, the door, a poster, etc.) which remained in the same position relative to the maze throughout the experiment.

Presurgical trahlhlg Subjects were habituated to the radial arm maze for 4 - 5 days by baiting all 8 arms of the maze with onehalf of a 'Froot-Loop' and allowing animals to explore the maze until all arms were visited. Presurgical training ensured that the subjects had explored all maze arms to approximately the same extent and also ensured that subjects ran rapidly down the maze arms for reinforcement.

Surgical procedures Following the last day of habituation, subjects received a lesion of one of the following cortical areas: (1) right A G m (RAGm) (n= 5), (2) left A G m (LAGm) (n = 5), (3) bilateral A G m (BAGm) (n = 5), (4) right PPC (RPPC) (n = 5), (5)left P P C (LPPC) (n = 5), (6) bilateral P P C (BPPC) ( n - 5 ) or (7) unilateral lateral agranular cortex (AGI, n = 10), which served as a surgical control group. For all subjects, surgery was performed within 48 h of the end of habituation training. The animals were anesthetized with sodium pentobarbital (65 mg/kg, i.p.) and when totally unresponsive, as determined by the absence of a corneal reflex, placed in a stereotaxic apparatus using blunt tipped ear bars. A bone flap was then removed over the appropriate brain region. For the A G m operates, the cortex extending from 2 mm posterior to 5 mm anterior to bregma and 2 mm lateral to the sagittal sinus was removed via gentle subpial aspiration with a fine gauge pipette, taking care not to damage the contralateral hemisphere. These lesions are

similar to those used in previous studies of spatial behavior (e.g. refs. 8, 37). However, in the study by Kesner et al. 27 which demonstrated an egocentric deficit in AGm-lesioned animals, lesions extended caudally only to bregma, leaving intact the most caudal aspect of AGm. Lesions of P P C were produced by aspiration of cortex overlying the corpus callosum and extended from 2 to 6 mm posterior to bregma and from 3 mm to 6 mm lateral to the sagittal sinus. Lesions included area 7 as defined by Kolb and Walkey 36. Unilateral lesions of lateral agranular cortex (AGI) served as control lesions and extended from 2 mm to 4 mm lateral and from 5 mm anterior to 2 mm posterior to bregma. The AGI lesions were adjacent to the A G m lesions in their medial extent and to P P C lesion in their posterior extent. These AGI operates served as a control for the effects of general cortical damage. In addition, because unilateral AGI lesions were at least as large as PPC and A G m lesions (see Results below), the unilateral AGI groups controlled for the possibility that any deficits found in subjects with A G m lesions compared to subjects with P P C lesions could be a function of lesion size rather than lesion locus. For all lesion groups, after all tissue was removed and hemostasis was achieved, the wound was gently packed with gelfoam and the incision sutured closed. The subjects were kept warm and monitored for postsurgical complications and then returned to the colony.

Postsurgical behavioral testing Assessment of egocentric spatial ability began within 48 h of surgery with the experimenter 'blind' with respect to the subjects' lesion locus. The paradigm employed was acquisition of the adjacent arm task which has been shown to be disrupted by bilateral A G m lesions but not P P C or sham lesions z7. Training consisted of placing the animal at the end of one arm of the radial arm maze and allowing it to visit only one other arm during a trial. Only the two arms adjacent to the start arm were baited. Beginning each daily trial from a different arm should make an allocentric solution (i.e. associate the reinforcement site with various environmental cues) to this task very difficult. In order to efficiently solve this task the animal had to learn an egocentric strategy (i.e. go to nearest arm(s) relative to its initial position in the maze). After being placed in the start arm, the animal was allowed to visit one arm (i.e. move down the length of the arm to the bait well) before it was removed from the maze and placed back in the home cage for I min. Animals were given five such trials per day. For each trial, the arm visited as well as the latency to reach the end of the arm was recorded. Visits to adjacent arms were scored as correct responses

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Fig. 1. Reconstruction of the largest (dark outline) and smallest (stipple) lesions for AGm, PPC, and control (AGI) groups on the radial arm maze task. A: reconstructions of left (L) and right (R) unilateral AGm, PPC, and AGI (control) lesions; and B: reconstruction of bilateral AGm and PPC lesions.

while visits to the remaining six arms were recorded as errors. The start arm was randomly determined on each trial, with the exception that animals were started from a different arm during each of the five daily trials. Animals were trained for 90 trials (5 trials per day for 18 days).

brain diagrams 4v without knowledge of the behavioral data. Lesion size was computed by overlaying each diagram with a grid of 1-cm squares and counting the number of squares either fully within or contacting the perimeter of the lesion representation.

Results Histology After training was complete, animals were overdosed with an i.p. injection of sodium pentobarbital (150 mg/ kg) and perfused transcardially with normal saline followed by 10% formalin. Brains were removed and fixed in 10% formalin. Forty-/Lm frozen sections were then taken, keeping every tenth section for staining with Cresyl violet. The thalamus was examined for any signs of gliosis, shrinkage of nuclei or calcification. Lesion extents were traced onto a series of standard coronal

Histology Examination of PPC, A G m and control (AGI) operates indicated that lesions removed the intended cortical areas and in the case of unilateral operates were limited to one hemisphere. As indicated in Fig. 1, PPC lesions removed the entire extent of area 7 (as defined by Kolb and Walkey36). In addition, PPC lesions caused slight damage medially to the retrosplenial cortex. Laterally, the lesions generally resulted in incom-

58 plete removal of PPC leaving approximately 1 mm of PPC intact, although several lesions did extend far enough laterally to damage areas 39 and 40. PPC lesions caused slight damage to somatosensory cortex anteriorly and visual cortex posteriorly. Ventrally, all PPC lesions resulted in damage to the underlying white matter. In one case the white matter was penetrated resulting in slight damage to the hippocampus. Although lesions of PPC in the current study were situated more caudally than in other studies of the effects of PPC lesions on spatial behavior z7"36, there is considerable overlap with lesions in these studies. In addition, the lesions in the current study are more consistent with the anatomical definition of PPC 36 than in those studies. Examination ofthalamic nuclei indicated slight to moderate areas of gliosis in the lateral posterior and lateral dorsal nuclei of the thalamus, although there was no indication of degeneration in the lateral geniculate nucleus. Therefore, although these lesions impinged on visual cortex, this damage was not extensive enough to result in any detectible retrograde degeneration in the thalamus. Examination of A G m lesions indicated rather homogenous lesions. As can be seen from Fig. 1, A G m lesions began slightly posterior to the frontal pole and encroached to varying degrees on retrosplenial cortex posteriorly. Laterally, AGm lesions generally result in some damage to AGI, although in most cases the damage was slight. Ventrally, most A G m lesions caused slight damage to the white matter (most often the cingulum). It is important to note that there was no obvious difference in the behavioral performance of those animals with lesions that included damage to white matter and those that did not. With the exception of one bilateral operate with slight unilateral damage to the underlying eaudate, A G m lesions did not penetrate the white matter. In addition, all A G m lesions encroached on the dorsal cingulate cortex to varying degrees with two lesions extending ventrally to damage the ventral anterior cingulate cortex. Examination of the thalamus indicated no evidence of shrinkage, gliosis, or calcification in any nuclei. Examination of control lesions (Fig. 1) indicated a similar anterior-posterior extent to that seen in A G m operates (e.g. beginning just caudal to the frontal pole and extending to the level of the retrosplenial cortex). Medially, most control lesions resulted in slight damage to AGm. As with A G m operates, examination of thalamic nuclei gave no indication of shrinkage, gliosis, or calcification. Analysis of variance indicated significant differences among the groups for lesion size (F6.32 = 3.3, P < 0.05). Subsequent Tukey's analysis comparing left A G m with

right A G m operates and left PPC with right PPC operates indicated no significant differences, suggesting any lateralized differences found in either the unilateral AGm or PPC groups was not due to the amount of cortex removed. In contrast, while control operates did not differ significantly from either left or fight AGm operates, controls did have larger lesions than both right and left PPC operates (P's < 0.05). Because A G m and PPC lesions removed the intended area, no comparisons of lesion size were made between these two groups. Behavior To determine if left and right control (AGI) operates could be combined into a single group, these groups were compared on all the variables of interest in the behavioral tests discussed below. These comparisons revealed no significant differences. Because no significant differences emerged between left and right AGI operates for the behavioral and lesion size measures, these groups were combined into a single control group for the analyses of behavioral data below. Behavioral training began 2 days following surgery. Most studies using such maze tasks have a longer period between surgery and the onset of training. However, with the exceptions of BPPC operates demonstrating a tendency to drag their hindlimbs during the first 3-4 days of testing and BPPC and BAGm operates demonstrating dexterity deficits in manipulating reinforcement during the first 2-3 days of testing, there was no evidence of a negative effect of the surgical procedure. In addition, a group • trial block ANOVA conducted on mean response time per trial resulted in no significant main or interaction effects and further indicates the lack of a detrimental effect of beginning training this soon after surgery. Percentage correct. All of the analyses are broken down into 9 trial blocks of 10 trials each (number of trials during a 2-day period). Initially, a group • trial block ANOVA was conducted on the percentage of correct responses to determine if any of the lesions resulted in a significant deficit on this task. This analysis indicated significant main effects for group (F6,32=5.7, P < 0 . 0 5 ) and trial block (Fs,256=11.7, P<0.05) as well as a significant interaction effect (/748,256 = 3.11, P < 0.05). Tukey's post-hoe analysis comparing BPPC, RPPC, LPPC and the pooled control group on the percentage of correct responses indicated no significant differences (Fig. 2). The finding of no deficit in either unilateral or bilateral PPC operates is consistent with the findings of Kesner et al. 27 who demonstrated no deficit on an identical task in bilateral PPC operates and supports the

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TRIAL B L O C K S Fig. 2. M e a n percentage of correct responses on the adjacent arm task. Each trial block is 10 trials (5 trials per day for 2 days). P P C groups (bilateral, right and left) and the control group are shown on the top. A G m groups (bilateral, right and left) and the control group are shown on the bottom. * Differs significantly from control operates, P < 0 . 0 5 . a Differs significantly from left and right A G m operates, P < 0 . 0 5 .

theory that PPC is not involved in egocentric spatial function. In contrast, BAGm operates were severely impaired on this task, as indicated by a significantly lower percentage correct than BPPC and control operates on the 3rd through 9th trial blocks (P's < 0.05) and relative to LAGm and RAGm on the 6th through 9th trial blocks (P's < 0.05). As can be seen from Fig. 2, BAGm operates showed little improvement during training. In addition, while demonstrating superior performance compared to BAGm operates, unilateral AGm operates also showed a deficit in learning this task compared to the remaining groups (Fig. 2). In particular, comparisons of RAGm, RPPC and control operates indicated that, whereas RPPC and control operates did not differ during any trial block, RAGm operates made significantly fewer correct responses than both RPPC and control operates on trial blocks 4, 5, and 6 (P's < 0.05). Comparison of LAGm, LPPC and control operates demonstrated a similar pattern of results. While LPPC and control operates did not differ during any trial block, LAGm operates showed a lower percentage of correct responses than both control and LPPC operates during trial blocks 5 and 6 (P's < 0.05).

As noted above, there was a significant main effect for trial block (F8,256 = 11.7, P<0.05) as well as a significant group • trial block interaction effect (F48.256 = 3.11, P < 0.05). As can be seen from Fig. 2, all non-AGm operates demonstrated a relatively steady improvement until the 4th or 5th trial block, where they reached asymptote at a 85-90.2/0 accuracy rate. While demonstrating a more gradual improvement than nonAGm operates, unilateral A G m operates also reached the same level of accuracy by the 7th trial block. In contrast, BAGm operates, while demonstrating a gradual improvement in performance, attained an accuracy rate of only 50~o by the last trial block. However, it is important to note that comparisons of the first and last trial blocks in individual groups revealed that, as with BPPC operates and all unilateral groups, BAGm operates had a significantly higher percentage of correct trials during the last trial block (P's < 0.05). Therefore, although showing a significant deficit relative to the remaining groups, BAGm operates demonstrated evidence of learning by the end of training. Hemispatialeffects. In order to determine ifunilateral lesions resulted in a response bias (i.e. visiting the three arms to one side of the start arm more frequently than the arms to the other side) a lesion group x trial block• side (ipsilateral vs. contralateral) ANOVA was conducted. Significant group x response side (F4.22=2.33, P < 0 . 0 5 ) and group x response side x trial block (F32,176 = 3.77, P<0.05) interaction effects were found. Tukey's post-hoc analyses indicated that, with the exception of R A G m operates, all unilateral lesion groups showed significantly more responses to ipsilateral arms during early trial blocks. In particular, control and left PPC operates had significantly more ipsilateral responses during the first trial block (P's<0.05), while left A G m and right PPC operates showed this ipsilateral response bias during the first two trial blocks (P's < 0.05). Animals with a unilateral lesion were also compared on the percentage of correct ipsilateral responses (i.e. the number of correct responses to the ipsilateral arm divided by the total number of responses to ipsilateral arms) and the percentage of correct contralateral responses. A trial block x group x side (ipsilateral vs. contralateral) ANOVA was conducted. Of particular interest in the above analysis are any significant main or interaction effects involving the side variable (i.e. any indication of decreased accuracy of responding to one side relative to the other). Analysis indicated that none of the effects involving the side variable reached significance. As can be seen from Fig. 3, the ipsilateral and contralateral percentage correct in the individual groups are virtually identical not only to each other but also to

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the total percentage correct (Fig. 2). It would therefore appear that, although causing a moderate deficit on the adjacent arm task, unilateral AGm damage does not result in a hemispatial deficit (i.e. does not result in a spatial deficit limited to the contralateral side). Discussion

Taken as a whole, the above analyses indicate that bilateral A G m lesions result in a severe deficit in learning the egocentric task. The results of the current study are similar to those found by Kesner et al. 27 and support the hypothesis that the prefrontal and posterior parietal cortices have dissociable spatial functions in regard to egocentric tasks. The role of A G m in egocentric tasks is further supported by the finding that the unilateral A G m groups learned the adjacent arm task more slowly than the other unilateral groups. However, the findings of (1)more correct responses in unilateral A G m operates as compared to the BAGm groups during later trial blocks and (2)no differences between unilateral AGm and other unilateral groups by the end of training indicate a less severe and long-lasting deficit in unilateral AGm operates relative to BAGm operates. It is interesting to note that even severely impaired

bilateral A G m operates demonstrated improvement on this task. Such a finding is in agreement with Kolb 32 who notes that, while disrupting learning on a number of spatial tasks, animals with bilateral A G m lesions generally learn these tasks, often to the level of normal animals. While bilateral AGm lesions in the present study resulted in a deficit throughout training (Fig. 2), these animals did show a steady improvement. It is therefore possible that, with a longer training period, animals would have reached a similar level of accuracy on this task to that seen in the other groups. The finding of an intermediate deficit following unilateral lesions like that found in unilateral A G m operates in the current study are rare in such maze learning tasks. Such a finding favors the interpretation that, at least in terms of the present task, the left and right AGm function additively (with neither side predominating) to produce efficient learning. While Loesche and Steward 41 demonstrated that unilateral lesions of entorhinal cortex resulted in a less severe deficit on a spatial alternation task than animals with bilateral entorhinal cortex lesions, few other studies have reported such an effect with unilateral lesions. While animals with unilateral lesions did demonstrate an ipsilateral response bias, no hemispatial deficit (i.e. a reduction in response accuracy limited to one side) was found in any of the groups with unilateral lesions. This contrasts with the findings of hemispatial deficits on complex perceptual and mnemonic tasks in humans with neglect L2. It is interesting to note that hemispatial memory deficits in humans were demonstrated for retrieval of items learned prior to injury. It may therefore be that if animals had received a lesion after acquisition rather than before on the above task that a deficit would have been demonstrated. However, Sutherland 5s reports that bilateral A G m operates demonstrate deficits on the acquisition but not the retention of some spatial tasks. Such findings suggest that tests of acquisition in AGm operates are more sensitive to the presence of spatial deficits and count against such an interpretation.

CHEESEBOARD glAZE

Materials and methods

SttbjecIs Subjects were 40 male Long-Evans hooded rats ordered from Harlan Industries and weighing 300-350 g at the time of testing. Animals were housed and maintained identically to subjects tested on the radial arm maze.

61

Apparatus and enviromnent The test of allocentric spatial ability was the cheeseboard task developed by Kesner et al. 27. The cheeseboard is a wooden circle 120 cm in diameter with 177 food wellsuniformly spaced throughout the board and recessed 1.25 cm into the floor. The maze floor and food wells were painted fiat black. The maze was located in the same room and position as described for the radial arm maze (see above).

Presurgical adaptation All animals were allowed to explore the cheeseboard with reinforcement (half of a 'Froot Loop') placed in one-quarter of the food wells during the 3 or 4 days just prior to surgery, presurgical adaptation ensured uniform exploration of the maze and active food searching behavior.

Surgical procedures Within 48 h of adaptation, the subjects received a lesion of one of the following cortical areas: (1)right A G m (RAGm)(n = 5), (2) left A G m (LAGm)(n = 5), (3) bilateral A G m (BAGm)(n = 5), (4)right PPC (RPPC)(n = 5), (5) left PPC (LPPC)(n = 5), (6) bilateral PPC (BPPC)(n=5), or (7)unilateral AGI (control, n = 10). The surgical procedures followed were identical to those used for the subjects in the radial arm maze.

an animal was placed on the edge of the board allowed to search until the baited well was found or 2 min had elapsed. During a trial day, the animal was started once from each of four points equally spaced around the perimeter of the cheeseboard. Animals were tested for 5 consecutive days. On the 6th day of training, the location of reward was changed to the middle food well in the diagonal quadrant and training continued for another 5 days as described above. This procedure of switching reinforcement has been used in studies on both the Morris water maze 36"43 and the cheeseboard 27 to test for memory of the original reward location and acquisition of a new location. Trials were videotaped and each path was drawn by an investigator 'blind' to the subjects' group membership. The length of each path to the site of reinforcement was traced and measured using an imageanalysis system (Bioscan Inc.). In addition, to the path length, each trial was evaluated for the degree of heading error. Heading error was determined by computing the angle between a line extending through the midline of animal's body after traveling approximately one body length from the starting point, and a line extending from the start point to the reinforcement site. At the end of training animals were perfused and brains processed identically to subjects in the radial arm maze.

Results

Postsurgical behavioral testing

Histology

Two days postsurgery acquisition training began on the cheeseboard task. This task requires the animal to learn the position of a food reward placed in one of the 177 food wells. The position of reinforcement was fixed from trial to trial and the animal began each trial from one of four different locations around the perimeter of the board. In order to efficiently solve this task, the animal must adopt an allocentric strategy (i.e. associate food location with surrounding environmental cues rather than take a fixed path). This task is considered to be a dry analog of the Morris water maze, although the tasks do differ in the type of reinforcement used (positive reinforcement for the cheeseboard and negative reinforcement for the water maze). The cheeseboard task is therefore not only likely to be less stressful to the animal, but utilizes the same type of reinforcement and has similar locomotor requirements to the radial arm maze. Each animal was pseudorandomly assigned a food well in the center of one of four quadrants of the cheeseboard which was baited during the first 20 trials of testing. During each test day the animal received 4 trials with a 1-min interval between trials. During each trial

The lesions and patterns of thalamic degeneration were very similar to those of subjects in the radial arm maze (Fig. 1). Analysis of variance demonstrated significant differences among the groups for lesion size (F6.32 = 9.7, P < 0.05). As with the subjects tested in the radial arm maze, Tukey's analysis comparing LAGm with RAGm and LPPC with RPPC operates indicated no significant differences. In contrast, while not differing significantly from either R A G m or LAGm operates, control operates had significantly larger lesions than both unilateral PPC groups (P's < 0.05).

Behavior As with the adjacent arm task, right and left control operates were compared on all the variables of interest below and demonstrated no significant differences and were therefore pooled to form a single control group. With the exception of BPPC operates showing a tendency to drag their hindlimbs during the first 3-4 days of training and BPPC and BAGm operates demonstrating dexterity deficits in manipulating reinforcement with their forepaws during the first 2-3 days of training, there was no indication of a detrimental effect of

62 beginning training this soon. In addition, all animals actively searched for and found reinforcement within 2 min of beginning the first trial of training. Path length. To determine if there was a deficit in any of the groups' ability to find the reward site, a lesion group x test day (1 through 10) ANOVA was conducted on the mean length ofpath to the baited well for the four daily trials. This analysis indicated significant main effects for group (F6.32=3.2, P < 0 . 0 5 ) and test day (F9,288=27.1, P < 0 . 0 5 ) but no significant interaction effect. Tukey's post-hoe analysis indicated that BAGm, LAGm, R A G m and control operates did not differ in the length of path to receive reinforcement during any of the 10 days of testing (Fig. 4). The finding of no deficit in either bilateral or unilateral A G m operates is consistent with that of Kesner et al. 27 and supports the theory that this area of prefrontal cortex does not function in the perception of allocentric space. In contrast, BPPC operates were severely impaired on this task, demonstrating significantly longer path lengths than both BAGm and control operates during the 2nd through 5ih trial days as well as the four trial days following the reversal trial (P's < 0.05) (Fig. 4). In 200. 0--0 ~--A

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trials. The vertical dashed line indicates the switchingof reinforcement to the diagonal quadrant. Bilateral (BAGm) and unilateral (LAGm and RAGm) AGm operates and control operates are shown on the top. Bilateral (BPPC) and unilateral (RPPC and LPPC) PPC operates and control operates are shown on the bottom. * Differs significantly from LPPC and control operates, P<0.05. ~ Differs significantlyfrom all other groups, P<0.05.

addition to the deficit found in BPPC operates, R P P C operates demonstrated a tendency towards intermediate path lengths during the trial days prior to the reversal trial (Fig. 4). In particular, R P P C operates had significantly longer path lengths during the 2nd and 3rd trial days compared not only to R A G m and control operates but L P P C operates as well ( F s < 0.05). RPPC operates did not differ significantly from the BPPC group during these trials. By the 4th trial day, the path lengths of R P P C operates had dropped to the level of LPPC, R A G m and control operates and were significantly shorter than B P P C operates until the end of training (with the exception of the reversal trial day) (P's<0.05). In contrast, L P P C operates had significantly shorter path lengths than BPPC operates throughout training ( F s < 0.05), while not differing from control or L A G m operates. Although bilateral PPC operates (and to a lesser degree R P P C operates) demonstrated significantly longer path lengths than the other groups, all groups showed considerable improvement by the end of training. In particular, as can be seen from Fig. 4, all groups demonstrated a sharp drop in path lengths by the 2nd day of training and maintained approximately the same level of performance until the reversal trial. Following the reversal trial, subjects again showed a steep drop in path lengths to a level maintained until end of training. That all groups had reached asymptote by the 2nd day is supported by the finding that path lengths for days 2 through 5 (which did not differ) were significantly shorter than those during day 1 (P's < 0.05). Similarly, all groups showed significantly shorter path lengths during trial days 7 through 10 as compared to the sixth trial day (i.e. the day when the reinforcement site was changed) (P's < 0.05). Reversal trial. That all groups (including R P P C and BPPC operates) had learned the general location of reward is further supported by analyses of the percentage of the run path which occurred in each quadrant during the reversal trial. All groups demonstrated similar patterns, with approximately 4 0 ~ of the run path occurring in the previously reinforced quadrant and the remaining 60~o of the path evenly distributed among the three remaining quadrants. Chi-square analyses performed on the data for each group confirmed the finding that a greater percentage of the run p a t h o c curred in the originally reinforced quadrant than would be expected by chance (control, Z z= 12.2, P < 0 . 0 5 ; BAGm, Z 2=21.03, P:<0.05; LAGm, Z2=9.77, P<0.05; RAGm, Z2= 13.28, P < 0 . 0 5 ; BPPC, Z2 = 9.88, P < 0.05; LPPC, Z 2 = 10.01, P < 0.05; RPPC, Z2= 12.2, P<0.05), indicating that all groups had learned the general vicinity of reinforcement.

63

Heading en'or. Previous studies have indicated that the poorer performance of PPC operates on such maze tasks may be due to a deficit in accurately using external cues to navigate. In particular, Kolb and Walkey 36 reported that PPC operates had a significantly greater initial heading error on the Morris water maze relative to controls. This deficit in PPC operates did not improve during training and was found even when the site of reinforcement was visible or marked by a large black rectangle. In order to determine if the deficit in PPC operates in the current st.udy might also be due to an inability to use external cues to navigate, animals were evaluated for the angle of movement (relative to the site of reinforcement) after having moved approximately one body length. A lesion group x trial day ANOVA indicated significant group (F6,32= 4.72, P<0.05), trial (F9.288= 16.1, P<0.05) and interaction effects (F54,288 = 6.32, P < 0.05). Subsequent Tukey's analyses indicated that BPPC operates had significantly greater heading errors relative to all groups (with the exception of RPPC operates) during test days 2 through 5 as well as the four trial days following the reversal trial (P's < 0.05). As can be seen from Fig. 5, RPPC operates tended to have an inter50 o--o

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mediate deficit in heading error during early trials, differing significantly from all but the BPPC group on the second trial day (P's <0.05) and not differing from any of the groups during trial day 3. By the 4th trial day, RPPC operates' heading errors were significantly smaller than BPPC operates ( P < 0.05) but did not differ from the remaining groups. Comparisons across trials in individual groups indicated that this deficit did not remit in BPPC operates. In particular, with the exception of BPPC operates, all groups showed a significant drop in heading error from the first to fifth and from the sixth to tenth trial days (P's < 0.05) indicating an improvement in the accuracy of navigation. As can be seen from Fig. 5, BPPC operates showed no such improvement in heading error. Consistent with the above analyses, examination of typical run paths revealed that, while non-BPPC operates generally took a direct path to the reinforcement site (Fig. 6A-D), BPPC operates often showed 'looping' behavior near the reinforcement site (Fig. 6E) or would initially overshoot the site (Fig. 6F). In addition, BPPC operates would often veer off an initially accurate heading (Fig. 6G) or show an inaccurate heading from the start (Fig. 6H). RPPC operates tended to show run paths similar to BPPC operates during early trial days but were indistinguishable from control operates by the end of training. In sum, the above analyses support the findings of recent studies which have demonstrated deficits following bilateral PPC damage on maze tasks which require use of environmental cues to navigate to reinforcement 27'36. It appears that BPPC operates learn the general vicinity of reinforcement, as indicated by a steep drop in the length of the path to reinforcement on the 2nd and 7th days of training and by an equal percentage of the run path in the originally reinforced quadrant during the reversal trial as the other groups. However, analysis ofheading errors indicates that BPPC operates are impaired in their ability to navigate accurately to the

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Fig. 6. Tracing of typical run paths for control operates ( A - D ) and bilateral PPC operates (E-H). The star represents the reinforcement site and the closed circle represents the start point for each trial.

64 site of reinforcement. In addition, it also appears that there are differences in the deficits between right "and left P P C operates, with R P P C operates having longer path lengths and greater heading errors during early trial days, while LPPC operates showed no such deficit. It is important to note that behavioral differences between right and left P P C operates cannot be explained by differences in lesion size (see Histology section above). Hemispatialdeficits. In order to determine if unilateral lesions might affect the accuracy of responding in a hemispatial manner, animals with unilateral lesions were compared on the length of path for those trials when reinforcement was contralateral to the start position and those trials when reinforcement was ipsilateral to the start position. A lesion group xtrial d a y • side of reinforcement (ipsi- vs. contralateral) ANOVA indicated no significant main or interaction effects involving the side variable. As can be seen from Fig. 7, the path lengths were very similar regardless of whether thestart point was ipsi- or contralateral to the reinforcement site and, as with the adjacent arm task, give no indication Of a hemispatial deficit (i.e. a deficit which was manifested only on trials when reinforcement was c0ntralateral to the start point).

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Discttssion The above analyses support the presence of a dissociation between A G m and PPC for the perception of allocentric space. In particular, the results of the current study are very similar to those of Kesner et al. 27, who demonstrated deficits in bilateral P P C operates on the cheeseboard task with no apparent deficits in bilateral A G m operates. In addition, the above analyses indicated that, while learning the general vicinity of reinforcement, B P P C operates are impaired in their ability to accurately navigate to the site of reinforcement. Such findings are consistent with that of Kolb and Walkey 36 who demonstrated a similar disruption in ' the accuracy of swim paths on the Morris water maze, even when the platform was visible or clearly marked by a black rectangle. Analogous disruptions in accurate motor behavior directed toward external stimuli are seen in monkeys with parietal lesions. In particular, it has been shown that monkeys with bilateral parietal lesions are impaired in their ability to return to their cage after being placed in the middle of the colony room (e.g. ref. 57). In addition, a number of studies have reported deficits in accurately reaching for stimuli (e.g. refs. 20, 39) following parietal lesions. All of the above findings point to a deficit in the ability to use external stimuli to guide motor behavior following a parietal lesion. In contrast to findings on the adjacent arm task, there were lateralized differences following unilateral PPC lesions on the cheeseboard task. In particular, R P P C operates demonstrated significant deficits during early trials which were not found following a L P P C lesion. While lateralized differences in emotionality tl have been reported in rats with left- and right-sided parietal lesions, to date no major study has demonstrated lateralized differences on maze behavior. A recent study did report deficits on the Morris water maze in rats with right but not left PPC lesions 42. However, these lateralized deficits were found only when P P C lesions were combined with corpus callosum section. It is important to note that R P P C operates did eventually reach the same level of performance as the control and L P P C groups, while BPPC operates demonstrated a deficit across the 10 days of training. It is not apparent from the above study whether the deficit in B P P C operates is due primarily to R P P C damage which fails to recover because of concomitant L P P C damage or whether combined left and right P P C lesions result in a more severe deficit than was found in R P P C operates. While these interpretations are not mutually exclusive (i.e. R P P C operates may have a less severe deficit which also recovers more quickly), the finding

65 that RPPC operates do not show a deficit relative to control operates following the reversal trial tends to support the idea that RPPC operates recover more quickly. The failure to find a deficit on this task in A G m operates, while consistent with the findings of Kesner et al. 27, contrasts with the conclusion of Kolb a2 that A G m lesions result in an impairment on all spatial maze tasks thus far tested. It is interesting to note that, in addition to the adjacent arm task, many studies of spatial behavior in AGm operates have utilized tasks which require the animal to learn a series of left-right turns s9, or remember the site of previous reinforcement 23"35. All of these tasks require knowledge of the animal's position (presently or in the past) to efficiently solve the task and therefore contain egocentric elements in their solution. It is importan~ to note that A G m operates also demonstrate deficits on the Morris water maze, a task which requires an alloc'entric solution 35. These findings are in sharp contrast to the failure to find a deficit in A G m operates on the cheeseboard task (ref. 27 and the current study), a task which appears to be analogous to the Morris water maze. Such discrepent findings may be related to the different types of reinforcement or motor requirements of these two tasks. It is noteworthy that the rodent prefrontal cortex has been shown to receive heavy dopaminergic input 18 and dopamine agonists have been shown to attenuate neglect in rats with unilateral A G m lesions 8"3~ In addition, placing animals in a tub of water has been shown to precipitate somatosensory deficits in rats depleted of dopamine 56. It may therefore be that the stress of swimming in the Morris water maze combined with the disturbance of the dopamine system following A G m damage result in a deficit not seen on a similar task which does not require the animal to swim (i.e. cheeseboard task). In addition, the disruption of normal swimming behavior seen in bilateral AGm operates 37 may contribute to a deficit in the water maze while not affecting performance on the cheeseboard task. Alternatively, failure to find a deficit on the cheeseboard task in the current study could have resulted from the smaller lesions in this study compared to Kolb et al. 35, rather than any difference in the maze task requirements.

GENERAL DISCUSSION

Allocentric-egocentric dissociation The results of the current study support the existence of an allocentric-egocentric dichotomy of function between A G m and PPC similar to that reported by Kesner

et al. zT. This dichotomy is not only supported by the findings in animals with bilateral damage but also subjects with unilateral cortical lesions. Such findings are consistent with findings in both human 4'54 and nonhuman primates 4s, which demonstrate a similar allocentric-egocentric dissociation of function between parietal and prefrontal cortices. It is important to note that both PPC and A G m operates eventually learn most spatial tasks, although not always to the level of control operates 32. Similarly, while deficits were found in A G m and PPC operates in the current study, all groups demonstrated significant improvement by the end of training. In addition, with the exception of the current study and Kesner et al. 27, it appears that damage to PPC or AGm results in deficits on the acquisition of most spatial tasks studied regardless of the strategy required to solve the task (i.e. egocentric, allocentric, or some other strategy) 32. Taken together, these findings suggest a lack of specificity in terms of PPC's and AGm's role in spatial behavior and would appear to count against the existence of a functional dissociation between these areas. However, such findings may be indicative of the fact that most spatial tasks can be solved using different strategies. When the cortical area mediating the optimal strategy is destroyed, less efficient strategies controlled by intact cortical areas may be used to solve the task, although learning will progress at a slower pace. A similar suggestion has been made by Kesner et al. 27 as an explanation for the finding that rats with medial prefrontal lesions actually learned the cheeseboard task faster than control operates. Kesner speculates that this facilitation resulted from the inability of rats with prefrontal lesions to form an egocentric strategy which would normally interfere with acquiring the optimal strategy.

Lateralized differences In addition to the egocentric-allocentric dissociation found, the current studY demonstrates lateralized differences between right and left PPC operates in their performance on the cheeseboard task. While lateralized differences have been reported in open field behavior 11 and on the Morris water maze 42 following unilateral parietal lesions, such differences were found only when lesions were combined with corpus callosum section. The current study is therefore one of the first to demonstrate a lateralized deficit on a complex maze task following unilateral damage limited to a cortical area in the rodent. The findings of such lateralized differences is another example in a growing body of evidence that lateralization of function is not a unique property of the human central nervous system (e.g. refs. 11-13, 61).

66

Hemispatial deficits While unilateral A G m operates showed an ipsilateral response bias on the radial arm maze and deficits were found on each maze task following either unilateral A G m or (right) PPC damage, there was no evidence of a hemispatial deficit on either task. This contrasts with the findings of neglect of contralateral stimuli found following unilateral A G m or P P C damage 9"29"3~ This finding also contrasts with the findings of hemispatial deficits on complex perceptual and mnemonic tasks in humans with neglect ~'2. However, in the case of hemispatial memory deficits in humans ~, neglect was demonstrated for retrieval of items learned prior to injury. It may therefore be that if animals had received a lesion following acquisition of these tasks a hemispatial deficit would have been found. However, Sutherland 5s reports that bilateral A G m damage results in deficits on the acquisition but not retention of spatial tasks. Such findings suggest that tests of acquisition are more sensitive to the :presence of spatial deficits (at least in the case of A G m operates) and counts against such an interpretation. Cortical vs. hippocampal spatial processing Taken as a whole, the current and other studies indicate that, as in the primate, discrete interconnected parietal and prefrontal areas play a major role in spatial processing in the rodent. Such findings are relatively recent, due primarily to the emphasis on the hippocampus in studies of spatial behavior in the rodent. A recent study has demonstrated that rats with bilateral P P C damage had significantly greater deficits on the Morris water maze compared to rats with bilateral lesions of the hippocampus ~5. Such findings suggest that not only do cortical areas function in spatial behavior, but on some spatial tasks may actually have a greater functional role than the hippocampus. It is important to note that there are differences in the spatial deficits following hippocampal and P P C or A G m lesions. In particular, while frontal and parietal lesions have generally been shown to disrupt the acquisition of maze tasks ~4'25'5s, animals with hippocampal lesions show both acquisition and retention deficits on similar tasks 15"43"5z. Such findings suggest that once a mapping strategy mediated by P P C or A G m is acquired, it becomes independent of that cortical area. In contrast, the function of the hippocampus in space appears to extend to the retrieval aspect of memory as well. PPC and A Gm as spatial processors In addition to the above behavioral findings, other evidence supports the role of PPC and A G m in the

perception of space. In particular, the anatomical findings of Kolb and Walkey 36 and Chandler et al. 5 indicate that PPC is a sensory convergence area for visual and somatosensory information, an organization which would seem to be requisite for an area involved in the perception of space. In addition, a recent study reported the presence of place cells in area 7 similar to those seen in rodent hippocampus 6. It is also important to note that lesions of P P C result in deficits on spatial tasks which are not mnemonic in nature, such as orientation to contralateral stimuli 29 or swimming to a visible platform 36. Such findings suggest that P P C is involved not only in memory for space, but basic spatial perception as well. Anatomical, physiological and behavioral data support AGm's role in spatial function as well. As with PPC, A G m is a sensory convergence area 49. In addition, it has now been well demonstrated that microstimulation of this area results in orienting movements of the head, eye and vibrissae, suggesting a role for A G m in accurate orientation to the environment 17't9. In addition, spatial deficits following A G m lesions are not limited to maze learning tasks, as indicated by the now well documented findings of hemispatial neglect following unilateral A G m lesions 7'8'6~. It would therefore appear that spatial deficits following A G m lesions are not due solely to a disruption of learning or memory, but a deficit in basic spatial processing as well. This is a particularly important point in terms of A G m function, as it has been demonstrated that lesions of prefrontal areas which include A G m result in memory deficits on non-spatial as well as spatial tasks (ref. 16; for review see ref. 32).

Cortical circuit for spatial behavior #z the rodent In addition to both A G m and PPC being sensory convergence areas, as in the primate, anatomical studies show these areas to be reciprocally connected 5"36"49'5~ In addition, both of these areas are reciprocally connected with the paralimbic area ventrolateral orbital cortex (VLO) 5"49"5~ With the exception of connections with visual cortex, the cortical connections of VLO are limited to P P C and A G m 51. When coupled with the findings of severe hemispatial neglect following unilateral lesions of VLO 3~, it appears that VLO may also be involved in spatial behavior. The results of the current study suggest that PPC, A G m and potentially VLO are components of a cortical circuit for spatial processing in the rodent which is analogous to that proposed for the primate z1'46.

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